The invention relates to novel processes and intermediates for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid.
The compound 1-(mercaptomethyl)-cyclopropaneacetic acid and its derivatives are important intermediates for the synthesis of leukotriene antagonists, which are useful in the treatment of asthma and other conditions mediated by leukotrienes, such as inflammation and allergies. A number of leukotriene antagonists are described in European Patent Nos. 480,717 and 604,114, and U.S. Pat. No. 5,270,324. Among the compounds disclosed in these patents are those which include a thiomethylcyclopropaneacetic acid moiety. This moiety is introduced using derivatives of 1-(mercaptomethyl)-cyclopropaneacetic acid.
A number of methods for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid are known, for example in U.S. Pat. Nos. 5,523,477 and 5,534,651. Most known syntheses for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid use either thiolacetic acid or hydrogen sulfide derivatives to introduce the mercapto function. Due to their strong disagreeable odour, the manipulation of these reagents and the corresponding synthetic intermediates is technically demanding. Further, essentially all the key intermediates in these syntheses are liquids or oils, which require either vacuum distillation or column chromatography for purification. In addition, the final step of each of these syntheses involves a hot basic hydrolysis in which the temperature may range from 80xc2x0 C. to aqueous reflux. Since 1-(mercaptomethyl)-cyclopropaneacetic acid is sensitive to oxidation, the use of such harsh reaction conditions may lead to reduced yields and/or product of unacceptable purity.
Therefore, the need exists for an improved process for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid.
In one aspect, the present invention provides a novel process for the preparation of 1-(mercaptomethyl)-cyclopropaneacetic acid which avoids the above-described disadvantages of known processes. In the process of the present invention, 1-(mercaptomethyl)-cyclopropaneacetic acid is prepared from 1-(hydroxymethyl)-cyclopropaneacetonitrile, which is commercially available or can be prepared by known methods from readily available reagents.
The process of the present invention essentially comprises four steps, the first step being the conversion of 1-(hydroxymethyl)-cyclopropaneacetonitrile to 5-oxa-spiro[2.4]hept-6-ylideneamine (also referred to herein as the xe2x80x9cimino esterxe2x80x9d) and acid addition salts thereof, which may be partially or totally converted to 1-(halomethyl)-cyclopropaneacetamide (also referred to herein as the xe2x80x9chalo-amidexe2x80x9d) under the reaction conditions.
The imino ester and halo-amide intermediates are preferably not isolated, but are reacted in situ with thiourea in the second step of the process to give the novel intermediate 1-(carbamimidoylsulfanylmethyl)-cyclopropaneacetamide, which is preferably isolated in the form of a solid acid addition salt, and optionally purified prior to further reaction.
In the third step of the process, 1-(carbamimidoylsulfanylmethyl)-cyclopropaneacetamide, or a salt thereof, is subjected to basic hydrolysis followed by oxidation in situ to form the disulfide of 1-(mercaptomethyl)-cyclopropaneacetic acid, a solid, which is preferably isolated and purified.
In the fourth and final step, the disulfide is reduced to 1-(mercaptomethyl)-cyclopropaneacetic acid.
Thus, the novel process for synthesizing 1-(mercaptomethyl)-cyclopropaneacetic acid provided by the present invention avoids the use of malodorous reagents such as thiolacetic acid and hydrogen sulfide derivatives, proceeds via solid intermediates which can be isolated and purified prior to further reaction, and avoids the use of a base hydrolysis as the final step in the process. The process according to the invention is therefore capable of producing 1-(mercaptomethyl)-cyclopropaneacetic acid of higher purity than known processes while using simpler techniques for handling reagents and for handling and purifying intermediates.
In another aspect, the present invention provides the novel intermediates 5-oxa-spiro[2.4]hept-6-ylideneamine and acid addition salts thereof and the corresponding 1-(halomethyl)-cyclopropaneacetamide, and a novel process for preparing these intermediates which essentially comprises the first step of the above-described process for preparation of 1-(mercaptomethyl)-cyclopropaneacetic acid.
In yet another aspect, the present invention provides the novel intermediate 1-(carbamimidoylsulfanylmethyl)-cyclopropaneacetamide and acid addition salts thereof, and a novel process for preparing this intermediate which essentially comprises the first two steps of the above-described synthesis for preparation of 1-(mercaptomethyl)-cyclopropaneacetic acid.
In yet another aspect, the present invention provides a novel process for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid disulfide which essentially comprises the first three steps of the above-described synthesis for preparation of 1-(mercaptomethyl)-cyclopropaneacetic acid.
The following is a detailed description of preferred processes according to the invention for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid.
As mentioned above, the starting material in the process of the present invention is 1-(hydroxymethyl)-cyclopropaneacetonitrile, which is known in the art and may be readily prepared according to known processes. For example, U.S. Pat. No. 5,523,477 discloses a method for preparing 1-(hydroxymethyl)-cyclopropaneacetonitrile from 1,1-cyclopropanedimethanol.
In the first step of the process of the invention, shown below, 1-(hydroxymethyl)-cyclopropaneacetonitrile (I) is treated with an acid to form the corresponding imino ester salt (II), which is partially or completely converted to the corresponding halo-amide (III) under the reaction conditions. 
The reaction depicted above is an example of a Pinner Synthesis, generally described in Pinner et al., Ber. 10, 1889 (1877); 11, 4, 11475 (1878); 16, 352, 1643 (1883).
Preferred acids for the reaction with 1-(hydroxymethyl)-cyclopropaneacetonitrile include those selected from the group comprising HBr, HCl, LiBr/H2SO4, NaBr/ H2SO4, KBr/H2SO4, KCl/H2SO4, NaCl/H2SO4 or LiCl/H2SO4. It is preferred that about 0.5 to 2 molar equivalents of the acid are used.
The reaction is preferably conducted in an inert solvent or a mixture of solvents, with preferred inert solvents being selected from the group comprising ethyl acetate, isopropyl acetate, acetone, methyl ethtone, methyl isobutyl ketone, propanol, butanol, isopropanol and t-butanol. The reaction temperature preferably ranges from about xe2x88x9210xc2x0 C. to about 25xc2x0 C.
In a particularly preferred embodiment of the invention, the acid comprises LiBr(1-1.2 eq)/H2SO4 (0.5-0.65 eq) and the inert solvent comprises isopropyl acetate. This combination produces the bromide salt of the above imino ester intermediate (II) and the bromo amide intermediate (III).
Preferably the intermediates (II) and (III) are not isolated prior to further reaction. Isolation is unnecessary since both species react in a similar manner in the second step of the process, now described below.
The second step of the preferred process, depicted below, comprises reaction of the intermediates (II) and (III) with thiourea to give a salt of 1-(carbamimidoylsulfanylmethyl)-cyclopropaneacetamide (IV), also referred to herein as the xe2x80x9camide-isothiuronium saltxe2x80x9d. 
Preferably, the second step of the process comprises addition of from about 1 to about 1.5 molar equivalents of thiourea to the reaction mixture of step 1 containing the imidate salt (II) and/or the halo amide (III). The reaction is preferably carried out in an inert solvent or a mixture of inert solvents, with preferred solvents including those selected from the group comprising acetone, ethyl acetate, isopropyl acetate, isopropanol, ethanol and toluene. The reaction temperature is preferably maintained at between about 40xc2x0 C. and the reflux temperatures of the solvent for a few hours. In a particularly preferred embodiment of the invention, the second step of the process is carried out in acetone at reflux.
After completion of the reaction, the reaction mixture is preferably cooled, resulting in precipitation of the amide-isothiuronium salt (IV) as a white to off-white solid precipitate along with inorganic salts produced during the first step of the. process. The yield of amide-isothiuronium salt (IV), calculated over the first two steps of the process, is typically from about 80% to about 94%.
In the third step of the preferred process, depicted below, the amide-isothiuronium salt (IV), which may also contain some inorganic salts produced during the first step of the process is first hydrolyzed under basic conditions. 
Preferred nucleohpiles for use in the hydrolysis include those selected from the group comprising alkali and alkaline earth metal hydroxides, for example, NaOH, LiOH, KOH, Ca(OH)2, Ba(OH)2 or quaternary ammonium hydroxides, with the use of alkali metal hydroxides being particularly preferred. The nucleophile is preferably used in excess, with 4.5 to 6.5 molar equivalents, and the reaction temperature preferably ranges from about 80xc2x0 C. to about 110xc2x0 C.
Hydrolysis of the amide-isothiuronium salt (IV) results in the formation of a 1-(mercaptomethyl)-cyclopropaneacetate salt (not shown), which is oxidized in situ to produce 1-[1-(carboxymethyl)-cyclopropanemethyldisulfanylmethyl]-cyclopropaneacetic acid, also referred to herein as 1-(mercaptomethyl)-cyclopropaneacetic acid disulfide, and having formula (V) shown above.
The oxidation is carried out using an oxidizing agent, preferably iodine or a peroxide selected from the group comprising hydrogen peroxide, t-butyl hydroperoxide and m-chloroperbenzoic acid. During the oxidation, the temperature of the reaction mixture is lowered to the range of about xe2x88x925xc2x0 to about 25xc2x0 C. Particularly preferred conditions for the oxidation comprise the use of from about 0.55 to about 0.7 molar equivalents of hydrogen peroxide solution. After the oxidation is complete, the reaction mixture is acidified to a pH of between 3.5 to 4.0, preferably using an acid selected from the group comprising formic acid, acetic acid, citric acid, hydrochloric acid, dilute sulfuric acid, KHSO4 and NaHSO4. A particularly preferred acid is aqueous formic acid. Precipitates of 1-(mercaptomethyl)-cyclopropaneacetic acid disulfide (V) are isolated by filtration. The crude product isolated as such usually shows xe2x89xa798% area purity by HPLC. Recrystallization using a solvent or a mixture of solvents selected from water, methanol, ethanol, isopropanol, acetone, ethyl acetate, isopropyl acetate, toluene, heptane, hexane and pentane, gives pure ( greater than 99% area by HPLC) disulfide compound (V). A particularly preferred solvent system is water-isopropyl acetate-heptane. Activated carbon may be involved during the recrystallization. 1-(mercaptomethyl)-cyclopropaneacetic acid disulfide is obtained as a white or off-white solid in 75% to 89% yield.
In the final step of the process, depicted below, the 1-(mercaptomethyl)-cyclopropaneacetic acid disulfide (V) is reduced to the corresponding 1-(mercaptomethyl)-cyclopropaneacetic acid (VI) by treatment with a reducing agent. 
Preferred reducing agents for use in the fourth step of the process include zinc/ammonium hydroxide and zinc/acetic acid. The system of zinc (1-1.3 molar equivalent)/ammonium hydroxide (4.5-5.5 molar equivalent) is particularly preferred. The reaction temperature preferably ranges from about 20xc2x0 C. to about 65xc2x0 C., more preferably from about 25xc2x0 C. to about 55xc2x0 C. Due to the sensitivity of the 1-(mercaptomethyl)-cyclopropaneacetic acid to oxidation, the reduction is preferably carried out under an inert atmosphere such as nitrogen or argon, and deoxygenated solvents and solutions are preferably used for the work up.
Upon completion of the reaction as detected by HPLC, the reaction mixture is filtered for clarification and the filtrate is acidified at lower temperatures, for example, from xe2x88x925xc2x0 to 25xc2x0 C. in order to achieve a pH of between 3.3 and 4. Suitable acids include formic acid, acetic acid, citric acid, hydrochloric acid, dilute sulphuric acid, KHSO4 and NaHSO4. The presence or absence of an organic solvent such as ethyl acetate, isopropyl acetate, methyl t-butyl ether, toluene or heptane does not affect the acidification. A particularly preferred combination of conditions comprises the use of citric acid/isopropyl acetate for the acidification at between xe2x88x923xc2x0 to 10xc2x0 C. until a pH of between 3.3 and 3.8 is obtained.
The 1-(mercaptomethyl)-cyclopropaneacetic acid obtained from the fourth step is then extracted with an organic solvent or mixture of solvents, preferably selected from the group comprising ethyl acetate, isopropyl acetate, methyl t-butyl ether, toluene or heptane. The organic layer is washed with water or aqueous sodium chloride or ammonium chloride solutions. It is then concentrated under reduced pressure at a temperature below 40xc2x0 C. to remove the solvent and traces of water. Heptane or hexane is then added and the mixture is slightly warmed (30-45xc2x0 C.) for the dissolution of the product. A filtration is performed to remove any insoluble impurities and salts. The filtrate is further concentrated in vacuo. Upon cooling, the product crystallizes. Isolation by filtration at between xe2x88x9210xc2x0 to 0xc2x0 C. followed by washes with cold heptane or hexane gives the 1-(mercaptomethyl)-cyclopropaneacetic acid as a white crystalline solid. The purity of the compound is usually 99.5% to 100% area by HPLC and the yield is from 70% to 88%. Apart from the possible presence of the corresponding disulfide, no single impurity is higher than 0.05% area by HPLC. Although generally not necessary, the compound could be purified by recrystallization with or without activated carbon in a deoxygenated solvent or a mixture of solvents, preferably selected from heptane, hexane, ethyl acetate, isopopyl acetate or methyl t-butyl ether.
Thus the present invention enables the preparation of highly pure 1-(mercaptomethyl)-cyclopropaneacetic acid via easily isolable and purifiable stable solid intermediates. Neither of the isolated intermediates, i.e. the amide-isothiuronium salt (IV) or the 1-(mercaptomethyl)-cyclopropaneacetic acid disulfide (V), present odour problems.
The invention is further illustrated by the following non-limiting examples. All procedures are carried out under an inert atmosphere (nitrogen).